Nuclear receptors are ligand-activated transcription factors that play important regulatory roles in human and mammalian physiology. We are interested in understanding the role of nuclear receptors in controlling lipid homeostasis. Our long-term goal is to elucidate the regulatory mechanisms controlling lipid homeostasis by nuclear receptors and to identify potential therapeutic targets for hyperlipidemia and coronary heart disease. Hepatocyte nuclear factor 4 is a member of the nuclear receptor superfamily and (HNF4 plays an important regulatory roles in bile acid, lipid and glucose homeostasis. Loss-of-function mutations in human HNF4 are associated with maturity-onset diabetes of the young 1 (MODY1), characterized by autosomal dominant inheritance and early onset diabetes. In addition, loss-of-function mutations in human HNF4 also cause disorders in lipid homeostasis, resulting in a reduction in plasma triglyceride and cholesterol levels. However, the mechanism underlying the hypolipidemic effect of HNF4 deficiency remains to be determined. In addition, the role of HNF4 deficiency in atherosclerosis has not been established. We hypothesize that HNF4 deficiency results in hypocholesterolemia via inhibiting multiple pathways of cholesterol metabolism and protects against the development of atherosclerosis. We will use mice deficient in hepatic Hnf4 together with biochemical, molecular and cellular approaches to determine the role of hepatic Hnf4 deficiency in de novo cholesterol synthesis, VLDL secretion, HDL biogenesis, reverse cholesterol transport and in protection against diet-induced hypercholesterolemia and atherosclerosis. Accomplishing the specific aims in this proposal will provide important insights into the mechanisms underlying lipid disorders in MODY1 patients, and will help us determine whether hepatic HNF4 is a target for treatment of hypercholesterolemia and coronary heart disease. PUBLIC HEALTH RELEVANCE: Atherosclerosis is the most common cause for coronary heart disease. Completion of the proposed studies will provide important insights into the mechanism underlying lipid disorders in MODY1 patients and will help us determine whether hepatic HNF4? is a therapeutic target for hypercholesterolemia and atherosclerosis. Thus, the studies proposed in this application are highly relevant to cardiovascular disease and human health.